Shizhifang ameliorates pyroptosis of renal tubular epithelial cells in hyperuricemia through inhibiting NLRP3 inflammasome

Traditional Chinese Medicine (TCM) Compound Shizhifang (SZF), consisting of the seeds of four Chinese herbs, has been used in Shanghai Shuguang Hospital in China for more than 20 years and has proven its clinical safety and efficacy in lowering uric acid and protecting kidney function.Hyperuricemia (HUA)-induced pyroptosis of renal tubular epithelial cells serves as a significant cause of tubular damage. SZF proves to be effective in alleviating renal tubular injury and inflammation infiltration of HUA. However, the inhibiting effect of SZF on pyroptosis in HUA still remains elusive. This study aims to verify whether SZF could ameliorate pyroptosis in tubular cells induced by uric acid (UA).Quality control analysis and chemical and metabolic identification for SZF and SZF drug serum were performed by using UPLC-Q-TOF-MS. In vitro, human renal tubular epithelial cells (HK-2) stimulated by UA were treated with SZF or NLRP3 inhibitor (MCC950). HUA mouse models were induced by intraperitoneal injection of potassium oxonate (PO). Mice were treated with SZF, allopurinol or MCC950. We focused on evaluated the effect of SZF on the NLRP3/Caspase-1/GSDMD pathway, renal function, pathologic structure and inflammation.SZF significantly restrained the activation of the NLRP3/Caspase-1/GSDMD pathway in vitro and in vivo induced by UA. SZF was better than allopurinol and MCC950 in reducing pro-inflammatory cytokine levels, attenuating tubular inflammatory injury, inhibiting interstitial fibrosis and tubular dilation, maintaining tubular epithelial cell function, and protecting kidney. Furthermore, 49 chemical compounds of SZF and 30 metabolites in serum after oral administration were identified.SZF inhibits UA-induced renal tubular epithelial cell pyroptosis via by targeting NLRP3 to inhibit tubular inflammatory and prevent the progression of HUA-induced renal injury effectively.